ESR

ESR
Erythrocyte Sedimentation Rate alias Sedrate.
The basic factors influencing the ESR have been understood since
early part of 20th century. The most satisfactory method of performing
the test was introduced by Westergren in 1921. Although there is an
enormous body of literature concerning the ESR, an elevated value
remains a nonspecific finding.
The erythrocyte sedimentation rate (ESR) determination is a simple
and inexpensive laboratory test that is frequently ordered in clinical
medicine.
The erythrocyte sedimentation rate (ESR), also called a sedimentation
rate or Biernacki Reaction, is the rate at which red blood cells
precipitate in a period of 1 hour. It is a common hematology test
which is a non-specific measure of inflammation. To perform the test,
anticoagulated blood is placed in an upright tube, known as a
Westergren tube, and the rate at which the red blood cells fall is
measured and reported in mm/h.
The test measures the distance that erythrocytes have fallen after one
hour in a vertical column of anticoagulated blood under the influence
of gravity. The amount of fibrinogen in the blood directly correlates
with the ESR.
The ESR is governed by the balance between pro-sedimentation
factors, mainly fibrinogen, and those factors resisting sedimentation,
namely the negative charge of the erythrocytes (zeta potential). When
an inflammatory process is present, the high proportion of fibrinogen
in the blood causes red blood cells to stick to each other. The red cells
form stacks called 'rouleaux' which settle faster. Rouleaux formation
can also occur in association with some lymphoproliferative disorders
in which one or more immunoglobulins are secreted in high amounts.
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Rouleaux formation can, however, be a normal physiological finding in
horses, cats and pigs.
When inflammation occurs the body produces proteins in the blood
which make the red cells clump together. Heavier cell aggregates fall
faster than normal red cells.
For healthy individuals, the normal rate is up to 20 millimeters in one
hour. Inflammation increases the rate significantly. Since inflammation
can be caused by conditions other than arthritis, the sedrate test alone
is not diagnostic. Sedrate can also point out to diseases involving other
organs.
Causes of a high ESR include:
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malignancy:
o malignant lymphoma
o carcinomas of colon and breast
haematologic:
o multiple myeloma - a high ESR plus osteoporosis equals
multiple myeloma until proved otherwise
o anaemia of acute or chronic disease, alone or combined
with iron deficiency anaemia - not Fe deficiency alone
o Macrocytosis elevates ESR.
connective tissue disorders - especially:
o systemic lupus erythematosus } normal in 5% of cases
o rheumatoid arthritis } patients
o polymyalgia rheumatica
o temporal arteritis
o systemic sclerosis
infections:
o tuberculosis
o acute hepatitis
o bacterial
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others:
o sarcoidosis
o renal diseases - especially with azotemia
o drug fever
o hepatic cirrhosis
o physiological increases in fibrinogen e.g. during pregnancy,
also raise ESR levels
The investigation of a patient with a high ESR and no clear
explanation should include the following:
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full blood count
Immunoglobulin electrophoresis or Immunoglobulin fixation
electrophoresis
Electrolytes
BUN
Creatinine
CRP
Anti-CCP antibody
radiography of the chest and abdomen
biopsy (e.g. bone marrow, temporal artery) may be indicated
Clinical Utility
The erythrocyte sedimentation rate (ESR) determination is a
commonly performed laboratory test with a time-honored role.
However, the usefulness of this test has decreased as new methods of
evaluating disease have been developed.
The test remains helpful in the specific diagnosis of a few conditions,
including temporal arteritis, polymyalgia rheumatica and, possibly,
rheumatoid arthritis. It is useful in monitoring these conditions and
may predict relapse in patients with Hodgkin’s disease.
Use of the ESR as a screening test to identify patients who have
serious disease is not supported by the literature. Some studies suggest
that the test may be useful as a ‘sickness index’ in the elderly or as a
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screening tool for a few specific infections in certain settings. An
extreme elevation of the ESR is strongly associated with serious
underlying disease, most often infection, collagen vascular disease or
metastatic malignancy.
When an increased rate is encountered with no obvious clinical
explanation, the physician should repeat the test after an appropriate
interval rather than pursue an exhaustive search for occult disease.
Physiologic Basis for the Test
TABLE 1
Reference Ranges for the ESR in Healthy Adults
Adults
Upper limit of reference range (mm/hr)
Age < 50 years
Men
Women
Age > 50 years
Men
Women
0 to 15
0 to 20
0 to 20
0 to 30
The basal ESR is slightly higher in females.
The widely used rule for calculating normal maximum ESR values in adults (98%
confidence limit) is given by a formula devised in 1983.
Children
Normal values of ESR have been quoted as 1to 2 mm/hr at birth, rising to
4 mm/hr 8 days after delivery, and then to 17 mm/hr by day 14.
Typical normal ranges quoted are:
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Newborn: 0 to 2 mm/hr
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Neonatal to puberty: 3 to 13 mm/hr, but some laboratories place an
upper limit of 20.
As with other laboratory tests, the actual reference range used for the
ESR should be established by the laboratory performing the test.
Women tend to have higher ESR values, as do the elderly. For unknown
reasons, obese people have also been noted to have slightly elevated
ESRs, although this is not thought to have clinical significance.
Any condition that elevates fibrinogen (e.g., pregnancy, diabetes
mellitus, end-stage renal failure, heart disease, collagen vascular
diseases, malignancy) may also elevate the ESR. Anemia and
macrocytosis increase the ESR. In anemia, with the hematocrit
reduced, the velocity of the upward flow of plasma is altered so that
red blood cell aggregates fall faster. Macrocytic red cells with a smaller
surface-to-volume ratio also settle more rapidly.
A decreased ESR is associated with a number of blood diseases in
which red blood cells have an irregular or smaller shape that causes
slower settling.
In patients with polycythemia, too many red blood cells decrease the
compactness of the rouleau network and artifactually lower the ESR.
An extreme elevation of the white blood cell count as observed in
chronic lymphocytic leukemia has also been reported to lower the
ESR. Hypofibrinogenemia, hypergammaglobulinemia associated with
dysproteinemia, and hyperviscosity may each cause a marked decrease
in the ESR. Although it has been reported that drug therapy with
aspirin or other nonsteroidal anti-inflammatory agents may decrease
the ESR, this has been disputed.
Because the ESR determination is frequently performed in office
laboratories, careful attention to technical factors that may produce
erroneous values is important (Table 2). A tilted ESR tube will cause an
artifactual elevation, whereas inadequate anticoagulation with clotting
of the blood sample will consume fibrinogen and may artifactually
lower the ESR.
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Researchers have wondered whether other tests, such as measurement
of C-reactive protein, may perform better than the ESR. Repeatedly,
the ESR and plasma viscosity determinations have been shown to be
the most satisfactory monitors of acute-phase response to disease after
the first 24 hours. During the first 24 hours in an inflammatory
process, C-reactive protein may be a better indicator of the acute phase
response. However, C-reactive protein tests are more expensive, less
widely available and more time-consuming to perform than the ESR.
Advantages and disadvantages of these three tests are summarized in
Table 3.
TABLE 2
Factors That May Influence ESR
Factors that increase
ESR
Old age
Female
Pregnancy
Anemia
Red blood cell
abnormalities
Macrycytosis
Technical factors
Dilutional
problem
Increased
temperature of
specimen
Tilted ESR tube
Elevated fibrinogen level
Infection
Inflammation
Malignancy
Factors that decrease ESR
Extreme leukocytosis
Polycythemia
Red blood cell abnormalities
Spherocytosis
Acanthocytosis
Microcytosis
Technical factors
Dilutional problem
Inadequate mixing
Clotting of blood sample
Short ESR tube
Vibration during testing
Protein abnormalities
Hypofibrinogenemia
Hypogammaglobulinemia
Dysproteinemia with
hyperviscosity state
Factors with no
clinically significant
effect or questionable
effect
Obesity
Body temperature
Recent meal
Aspirin
NSAIDs
NSAIDs = nonsteroidal anti-inflammatory drugs; ESR = erythrocyte sedimentation rate.
Using the ESR to Make a Diagnosis
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The ESR remains an important diagnostic criterion for only two
diseases: polymyalgia rheumatica and temporal arteritis (Table 4).
Polymyalgia rheumatica is characterized by severe aching and stiffness
in the neck, shoulder girdle or pelvic girdle areas. In some patients,
systemic symptoms may predominate, with initial manifestations
including anemia, fever of unknown origin or a nonspecific systemic
illness accompanied by anorexia, malaise and weight loss.
Temporal arteritis is usually characterized by headaches, visual
disturbances such as blindness, a tender, reddened or nodular temporal
artery, facial pain and jaw claudication. Extra-cranial vasculitis
sometimes is associated with temporal arteritis and may present with
symptoms affecting the liver, kidneys or peripheral nervous system.
Systemic manifestations including anemia, fever, weight loss, malaise
and an abnormal alkaline phosphatase value are frequently present.
Nearly all patients who have temporal arteritis will have an elevated
ESR; however, an occasional patient may present with a normal value.
One study found that the average ESR was greater than 90 mm per
hour in patients who had temporal arteritis, with values exceeding 30
mm per hour in 99 percent of the cases. However, if there is solid
clinical evidence of temporal arteritis, a normal ESR value should be
disregarded, and the patient should undergo a temporal artery biopsy
or an empiric trial of corticosteroid therapy.
The ESR traditionally has been a diagnostic parameter for rheumatoid
arthritis, but it is used as a means of staging the disease rather than as
one of the major diagnostic criteria. The American Rheumatism
Association criteria include an elevated ESR as one of 20 findings that
may be present. Most rheumatologists believe that careful joint
examination confirming synovitis constitutes a more important
diagnostic criterion. However, the ESR may still be useful if the
diagnosis is questionable and definite evidence of inflammation might
affect therapeutic decisions.
Monitoring disease activity or response to therapy
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TABLE 3
Comparison of the ESR, Creactive Protein and Plasma
Viscosity Tests
Test
Advantages
Disadvantages
ESR
Inexpensive,
Affected by a
quick, simple to variety of
perform
factors,
including
anemia and red
blood cell size;
not sensitive
enough for
screening
CMost rapid
Wide reference
reactive response to
range may
protein inflammation
necessitate
(complementary sequential
to ESR in this recording of
regard)
values,
expensive,
batch
processing may
delay individual
results
Plasma Unaffected by Expensive, not
viscosity anemia or red widely
blood cell size available,
technically
cumbersome to
perform
ESR = erythrocyte sedimentation rate.
In the past, the ESR was commonly used as an index of disease activity
in patients who had certain disorders. With the development of more
specific methods of evaluation, the ESR has remained an appropriate
measure of disease activity or response to therapy for only a few
diseases: temporal arteritis, polymyalgia rheumatica, rheumatoid
arthritis and, possibly, Hodgkin’s disease.
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In following the response to therapy in temporal arteritis and
polymyalgia rheumatica, the ESR may not always give a clear indication
of disease activity. Therefore, patients should be monitored by ESR
values and clinical findings. For example, when corticosteroid therapy
is started for temporal arteritis or polymyalgia rheumatica, the ESR
usually drops within a few days. In many patients the ESR will stop at
a higher-than-normal level, even if the patient’s clinical status has
dramatically improved. For this reason, an elevated ESR in a patient
who has established temporal arteritis or polymyalgia rheumatica
should not be used as the sole rationale for maintaining or increasing
steroid therapy if the patient is doing well clinically. The converse is
also true, because clinical relapse can occur in the face of a normal
ESR finding.
In rheumatoid arthritis, the ESR tends to reflect clinical disease activity
but usually mirrors other symptoms such as morning stiffness or
fatigue. Joint examination is considered more useful in assessing
synovitis. In one study, the ESR level that best distinguished patients
with rheumatoid arthritis in remission from those with active disease
was less than 20 mm per hour for men and less than 30 mm per hour
for women. However, other studies have shown that a significant
proportion of patients in clinical remission may still have an elevated
ESR value.
Cancer
In oncology, a high ESR has been found to correlate with overall poor
prognosis for various types of cancer, including Hodgkin’s disease,
gastric carcinoma, renal cell carcinoma, chronic lymphocytic leukemia,
breast cancer, colorectal cancer and prostate cancer. In patients with
solid tumors, a sedimentation rate greater than 100 mm per hour
usually indicates metastatic disease, but for most tumors this relatively
nonspecific finding has been supplanted by more precise diagnostic
tests. However, European studies of patients with Hodgkin’s disease
have suggested that an elevated ESR may still be an excellent predictor
of early relapse, especially if the value remains elevated after
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chemotherapy or fails to drop to a normal level within six months after
therapy. Certainly, an increased ESR should never be used as the sole
criterion for diagnosing relapsed Hodgkin’s disease.
Discriminating Iron Deficiency from Anemia of Chronic Disease
TABLE 4
Utility of the ESR: Key
Considerations
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The ESR is an inexpensive,
simple test of chronic
inflammatory activity.
Indications for the ESR have
decreased as the sophistication
of laboratory testing has
increased.
The ESR rises with age, but this
increase may simply reflect a
higher disease prevalence in the
elderly.
The use of the ESR as a
screening test in asymptomatic
persons is limited by its low
sensitivity and
specificity.
An elevated ESR is a key
diagnostic criterion for
polymyalgia rheumatica and
temporal arteritis, but normal
values do not preclude these
conditions.
When there is a moderate
suspicion of disease, the ESR
may have some value as a
"sickness index."
An extremely elevated ESR
(>100 mm/hr) will usually have
an apparent cause--most
commonly infection, malignancy
or temporal arteritis.
A mild to moderately elevated
ESR without obvious etiology
should prompt repeat testing
after several months rather than
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an expensive search for occult
disease.
ESR = erythrocyte sedimentation rate.
The ESR may be useful in differentiating iron deficiency from anemia
of chronic disease in patients with a background chronic inflammatory
condition such as rheumatoid arthritis. Iron deficiency anemia and
anemia of chronic disease are hypo-regenerative and characterized by a
low reticulocyte count. Unfortunately, neither iron studies nor serum
ferritin levels are definitive in distinguishing between these two types
of anemia. Because both may have a transferrin saturation of around
15 percent, simply evaluating the serum iron level and percent
saturation will not differentiate between the two conditions. Similarly,
an individual serum ferritin level may not be helpful when
inflammation is present because ferritin is an acute phase reactant and
may be artifactually elevated.
Screening for Systemic Disease or Neoplasia
Unfortunately, the ESR is neither sensitive nor specific when used as a
general screening test. For instance, the ESR may be elevated in the
presence of infectious disease, other inflammatory or destructive
processes, collagen vascular disease or malignancy, but it may not be
increased in a number of infectious diseases (e.g., typhoid fever,
malaria, mononucleosis), allergic processes, angina (as opposed to
myocardial infarction) or peptic ulcer disease (as opposed to active
inflammatory bowel disease).
Because an elevated ESR may occur in so many different clinical
settings, this finding is meaningless as an isolated laboratory value. In
addition, some patients who have malignant tumors, infections or
other inflammatory disorders will have normal ESR values. Most
unexplained ESR elevations are short-lived and not associated with any
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specific underlying process. In those instances where disease is present,
it will usually be obvious after completion of history taking, physical
examination and collection of routine laboratory data.
Although an elevated ESR may occur with many types of cancer, it
rarely indicates an occult tumor because most of these patients have
widely metastatic disease. For this reason, when a mild to moderate
elevation of the ESR (less than 100 mm per hour) is encountered in an
asymptomatic patient, simply repeating the test at some future time
should be considered in the absence of other clinical findings. No
evidence suggests that an elevated ESR that is unsubstantiated by
history, physical examination or other findings should trigger an
extensive laboratory or radiographic work-up or invasive diagnostic
procedures.
Screening for Infection in Specific Clinical Settings
Recent studies have evaluated the ESR as a screening test for infection
in specific clinical instances such as infection associated with
orthopedic prostheses, pediatric bacterial infection and gynecologic
inflammatory disease. Although frequently abnormal in patients who
have an infected prosthesis, the ESR value is not as sensitive or
specific an indicator of infection as joint aspiration.
Elevation of the ESR has been proposed as a clue to the presence of
an invasive bacterial infection in children after the first 48 hours of
symptoms. In one investigation, the ESR more accurately indicated the
severity of acute pelvic inflammatory disease than did the physical
examination, thus helping to evaluate patients who required
antimicrobial therapy. The appropriateness of the ESR as a screening
test for infection, even in these well-defined clinical settings, requires
further evaluation.
Usefulness as a sickness index in the elderly
Some authors have proposed that the ESR be used as an inexpensive
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term care hospital who had a nonspecific change in health status or
developed new musculoskeletal complaints, the post-test probability of
new disease rose from 7 percent in those with an ESR of less than 20
mm per hour to 66 percent in those with an ESR of more than 50 mm
per hour. However, this investigation specifically excluded patients
known to have an ESR-elevating disease and those in whom no disease
was suspected.
The authors concluded that combining clinical evaluation with an
individual ESR value allowed the identification of groups of patients in
whom the likelihood of disease was quite low or reasonably high,
possibly limiting unnecessary investigations.
Elevated ESRs, while more prevalent in the elderly than in younger
individuals, have a similar pathological significance. But as clinical
conditions in the elderly are usually obscure, we should be more
careful to investigate the issue of high ESR in geriatric population,
even when they are asymptomatic.
Extreme Elevation of the ESR
An extreme elevation of the ESR (defined as greater than 100 mm per
hour) is associated with a low false-positive rate for a serious
underlying disease. The conditions found in this situation have varied
in individual populations, depending on patient age and inpatient
versus outpatient status. In most series, infection has been the leading
cause of an extremely elevated value, followed by collagen vascular
disease and metastatic malignant tumors. Renal disease has also been a
notable etiologic factor.
Because most of these conditions are clinically apparent, any tests
performed should be clinically driven. For instance, if symptoms of
infection are present, the appropriate cultures, including urine and
blood, and skin testing for tuberculosis should be obtained. An
exhaustive search for an occult malignancy should not be undertaken
because, if cancer is present, it is almost always metastatic.
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No obvious cause is apparent in fewer than 2 percent of patients with
a markedly elevated ESR. In such patients, the history and physical
examination coupled with readily available tests will usually establish
the etiology. Because a notable number of patients with an ESR greater
than 100 mm per hour have myeloma or some other type of
dysproteinemia, urine and serum protein electrophoretic studies should
be included in the testing.
Relation to C-reactive protein
C-reactive protein is an acute phase protein that is produced by the
liver during an inflammatory reaction. Since C-reactive protein levels in
the blood rise more quickly after the inflammatory or infective process
begins, ESR is often replaced with C-reactive protein measurement.
There are specific drawbacks, however, as they were found to be
independently associated with a diagnosis of acute maxillary sinusitis
so that the combination of the two measurements improved diagnostic
sensitivity and specificity.
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